ABSTRACT Health disparities in the incidence and prognosis of breast cancer (BC) in African American and Hispanic populations have been at least partly attributed to genetic factors that distinguish these populations. Our long-term objective is to understand how inter-population and inter-individual genetic variations modulate BC risk. In our previous work, we have used admixture mapping in the population of Puerto Rico to identify regions of the genome predisposing to BC. This has led to the identification of three susceptibility loci (7p15.3, 10q21.1 and 14q24.1), two of which have not been reported before. Interestingly, African ancestry at the 10q21.1 locus was associated with an increase risk of triple negative negative tumors, which lack the expression of the estrogen (ER), progesterone (PR) and human epithelial growth factor (HER2) receptors and is known to be associated with a poor prognosis. In this renewal application, we propose to pursue this work as follow. In Specific Aim #1, we will identify common and rare genetic variants within the admixture signals by association analysis of a dense array of single nucleotide polymorphisms (SNPs) and targeted sequencing. In Specific Aim #2, we propose to identify the genomic regions involved in determining the somatic characteristics of breast tumors by conducting admixture mapping of breast tumors stratified by expression subtype and common mutation status. In Specific Aim #3, we will further explore the genetic factors involved in BC susceptibility in Puerto Rico by performing a replication study of known genome-wide association study (GWAS) loci. This application proposes an integrated and innovative strategy to improve our understanding of the role of genetics in BC and it targets a Hispanic population, which is often underrepresented in genetic and genomics studies. With the discovery of common genetic variants that may cumulatively identify the extremes of the risk distribution, one can begin to envision precision prevention of breast cancer by balancing the level of risk with appropriate risk reduction interventions. The results from the proposed study can contribute importantly to this goal. The proposed project is expected to have a positive impact on the PI's career by providing the basis for the preparation of high quality manuscripts that will lead to R-type funding. Dr. Dutil is well trained in molecular genetics and genomics and is surrounded by a strong multidisciplinary team: Dr. Massey is an expert in bioinformatics applied to genomic data; Dr. Ziv is a leader in the field of statistical genetics and admixture mapping; and Dr. Fejerman is a pioneer in using BC admixture and GWAS in Latina populations.